Alkaminesters of the p-aminobenzoic acids and process of making same



one min, norm Amr assrexoa ro ram: mm

LUCIU'I G name, EOGKST-OR-THE-IAIIQGQA OOBPOM'IION 01' Io Drawing.

To'allwhoms't concerns Be it known M, 0m Emma, a citizen of Germany,residing at Hofheim am Taunus, Germany, have invente'dcertain new 5 anduseful Improvements in Alkaminesters of the p-Aminobenzoic Acids andProcesses of Making Same, of which the followmg 1s a specificatiom I Ihave found that by esterlfymg N monoalkyland N-monoalkylogalkilerivatives if the obenzoic aci wit amino alcois an esteis a ording tothe usual ods, alkaminesters are obtained which,

1: ed by their excellenteflicacy as agents for producing surfaceanaesthesiaand which, as numerous comparative tests have proved, are byfar superiorto cocaine their active ower. The new as Y sroducts co 'tutetypica agents for proamesthesia and are, there- 4 fore, in the firstplace suitable for anaesthetlzing the large complex of the mucous mem-25 The new bodies correspond to the formula:

' .m in R standslfor anlkyallkamine' id'esidue an 'oran ora oxyres1ue. x

The product o nmy be obtained by replacin aminobenzoic acid in anydesired b iser t hydrogen atom-ef'the-carboxyl fioup b an alkamineresidue and by fur- 0 er re ing a h dnogen atom of the amino group y analky or alkyloxyalkylresidue containing more than two carbon atoms andthen converting the basesthus obtained into theirsalts. I. i Thefollowing examples serve to illustrate myuiiaventiiqm: be d B dropylammo nzcic' aci 1 ethylam oet yleateri p-N- -pro ylaminobenzoicacid may be obtained in e same way the p-aminobenzoic duced byor'mr-anmosmzorc acniam 1:. or name sum.

. Application filed January 5, 1925. m1 He. can.

as Houbenand-Freund (Ber. 46, 3835) prescr bed for the reparation ofp-isoamylammobenzoic aci VIZ by boiling an aqueous solution ofpotass'umaminobenzoatewith n-pro ylbromide. en purified by re crystaization from benzene the product melts at 165168. By titration therewere found the molecular weight 178; calculated 179 for C H ,O,N'.

Equimolecular-quantities of pro ylaminobenzoic acid and fl-dieth laminoet ylalcohol are dissolved or suspen ed in 10 times their wei t, oftoluene; the mixture is saturated wit hydrochloric acid gas and heatedin an oil bath of about 150? while a current of hydrochloric acid gas isslowly assed through it so that toluene slowly istills over. Alon' withtoluene the water pma esterification distills over. Duration about 8hours. In order to work up the product some water is added after coolinguntil the salt is dissolved; the layer of toluene is separated and thebase of the ester precipitated from the aqueous solution by means ofa-solution of sodium carbonate. v y-treating the oily base in ether,drying 76 over potassium carbonate and adding alcoholic hydrochloricacid to the solution until it shows a neutral reaction on litmus, themonohydrochloride (M. P. 103-104") is obtained in the form of a colorlexcrystalline powder.

Analysis: 0 ,H O DLCI: Calculated 8.92% Fqund=' 8.75% Gin-11.27% =11.29%32.) p-N-B-metho I ethylaminobenzoic aci -B-diethylaminoeth y ester:p-N-(5-methoxymethylaminobenzoic acid is produced by bollin an aqueoussolution of sodium pamino nzoate with (5-ch1oreth lfmethyl- 00 ester..The product separating uring the reaction is o tained in a pure stateby recrystallization from alcohol. Melting oint 159161. Molecular weightcalcu ated C-,,H,,O,N 195, by titration found 191.

A mixture of p-N-fi-methoxyethylaminobenzoic acid and ten times itsweight of ethylene chlorhydrine is saturated without sodium carbonate,

cooling with hydrochlorid acid gas and maintained for some hours at atem erature of the water bath. By distilling o the excess of ethylenechlorohydrine in vacuo, decomposing the residue with a solution oftreating the oil with ether, drying over potassium carbonate anddistilling o the ether, there is obtained methoxyethylaminobenzoicacid-t-chloro ethylester. The latter is immediately transformed into the[i-diethylaminoethylester by boiling it for 10 hours using. a condenserwith a little more than 2 molecules of diethylamine. For the isolationof the {i-diethylamino-ethylester the reaction product is disolved in anexcess of. diluted acetic acid, precipitated with a solution of sodiumcarbonate and the oil is treated with ether. The product is then driedover potassium carbonate and distilled. Boiling point 9 2t5. The oil iscolorless and odorless. The monohydrochloride is obtained by dissol theester in the equimolecular quantity o alcoholic h drochloric acid and bymixin itwith et er. It forms colorless cry'sta s of the boiling point86.

Analysis: O, H ,O N Gl: Calculated N=8.49% Found=8.19%

(3.) p-N-allylaniinobenzoic acid-(i-diethyl-aminoethylester: By shakingfor some hours an aqueous solution of sodium p-aminobcnzoate with allylbromide a thick crystalline magma of p-N-allylaminobenzoic acid isobtained which b recrystallization and repreci itation from ene caneasily .be produ in a pure state; melting point lee-146. Molecularweight calculated for C H O N 177, found by titration 179.

The ethyl ester is produced by boiling the acid with alcohol andsulfuric acid under reflux and pouring the solution in an excess I of acold solution of sodium carbonate, whereupon it separates in a solidform. When recrystallized from benzene, it shows a melting point of -62.

When the p-N-allylaminobenzoicacid ethylester is boiled withB-diethylaminw ethylalcohol while adding a small quantity of sodiumethylate, a replacement of alkyl occurs and ethyl alcohol distillso'ver. By asu uent distillation .in vacuo the fii-di- Iethylamino-ethylester is obtained as a feebly yellowish oil; boilingpoint 10 mm. 232.

= Analysis for C H O N Calculated N=10.16%

Found =10.00% (4.) p-N-propylaminobenzoic acid'y-diethylamino-propylester: p-N-propylaminobenzoic acid ethylester(obtained in the known manner from the acid by wa of esterification withethyl alcohol, in ting point and -y-diethylamino-praoi lal hol in excessare heated while a Analysis: C .,H O N Cl: Calculated N 8.52 Found:8.30% 01:10.79 =10.s9%

(5.) p-N-isoamylaminobenzoic acid diethylaminoethylester: p-N-isoamlaminobenzoic acid ethylester-obtained om the acid as a crystallinemass, melting point 68, (Comp. Houben and Freund Ber; 46 (1913) 3833) byboilin with ethylalcohol contain ing hydrogenchloride and subsequentlydecomposing the product with a solution of sodium carbonate-is slowlyheated with the {i-diethylamino ethylaleohol in excess and with a smallquantity of sodium ethylate servin as a catalyzer. Ethylalcohol splitsofl" an distills over. tion' product is dissolved in diluted aceticacid, any unaltered ethylester which may still be present is removed bysubject-in the solution to a treatment with ether, and thediethylaJnino-ethylester is separated by supersaturating 1e aqueoussolution w1th a solution of 'sodium carbonate. is treated with ether,dried over potassium carbonate and distilled from all substances whichseparate in vacuo at a temperature of the water bath. The remainingp-N-iso' amylaminobenzoic acid ii-dietliylaminoethylester forms an oilof a light brownish color and is entirely pure.

Analysis: C I-1 05151 Calculated C=70.52% H: 9.87% N: 9.17%

((21 p-N-propylaminobenzoic acid B-piperi 'no-ethylester: A mixture fromp-N- propylaminobenzoic acid ethylester and fi-piperidino-ethylalcoholin excess after addition thereto of a small quantity of sodium ethylateis heated, whereupon ethyl alcohol is-split off and distills over. Theproductof the reaction is, then treated with alcohol, neutralized withalcoholic hydrochloric acid while cooling and from the filtered solutionthe monohydroohloride is precipitated. The product, which at first comesout as an oil Found=70.33% =10.29% 8.88%

The remaining reac- The solution but soon solidifies when triturated, isobtained in an entirely pure state by recrystallization from a mixtureof alcohol and acetic ester. Melting point 157158.

' hydrochloride is p '1 holic hydrochloric acid I 60 (7.) p- N 5-methoxyethylaminobenzoic acid fi-piperidino-ethylestcrz A misture ofp-N-fl-methoxyethylaminobenzoic acid ethylester (obtained from the acid1n the usual manner by estcrification withethyl alcohol, an oil ofboiling point 8 mm. 199-200") and (5- piperidino-ethylalcohol to whicha. small quantity of sodium ethylate is added as a catal st, is boiledso that the ethyl alcohol whic splits ofi' distills over. By furtherworking up the product of the react on In the manner indicated inexample 6, the monohydrochloride of the p-N-fi methoxyethylaminobenzoicacid fi-pipendmo-ethylester is obtained as a oolorles crystalhne powdermeltingat 138.

Analysis for C H O N Glz Calculated G=59.53% Found=59.40% H=- 7.95%7.91% N: 8.18% 8.21% G1=-10.35% =10.24% (8.) p-N-propylaminobenzoic acidfi-diethylamin'o-ethylester: 'Equimolecular quantities of pdaminobenzoicacid B-diethgiaminoethylester and-propyl bromide are iled in the oilbath for 5 hours under reflux and while adding ropyl alcohol as adiluting nt. The soutlonremains homo eneous w en, after cooling, wateris added ereto; it gives a neutral or slightly acid reaction whichproves that all of the base has been converted into a salt. Foreliminating the propyl alcohol the solution is treated with ether andthen supersaturated with a dilute solution of sodium carbonate. Thealkaminester is thus separated as an oil, whilst simultaneously formedquaternary ammonium salts remain in solution. After treating the productwith ether and drying the ethereal solution over sodium carbonate thereis obtained by fractional distillation in vacuo thep-N-propylaminobenzoic acid diethylzamino-ethy ester as anoil boiling at217 under 7 mm. ressure. The monouoed by mixing the base with anequimolecular quantity of alcoand precipitating it with ether afterrecrysta lization from acetone it shows a melting point of 103-104. Itforms a colorless crystalline powder.

9.) 'p N {5 methoxyethylaminobenzoic acid B-dieth lamino-ethylester: Amixture consisting 1 molecule of p-aminobenzoic acidfi-diethylamino-ethylester, 1, 1 inolecule of fi-chlomethylmethyletherand about twice the quantity by weight of ethylene glycolthe latter asa. diluting agent-is boiled in an oil bath for several days underreflux. To

the mixture is added water and it is then shialzen'with ether whereinthat part of the parent material which has not entered into reaction isdissolved. On addition of a solution of sodiumcarbonate an oilprecipitates ing with ether the monohydrochloride is obtained which soonsolidifies recrystallization from formic acid ethylester mes entirelypure, forming a colorless crystalline powder melting at 86. 1

I claim: 1. The process for preparing alkaminestors of the p-amino I 01cacids monosubstituted at the nitrogen having the formula:

and which, by

wherein R stands for an alkamine residue and R for an alkyl-oralkyloxyresidue, which consists in substituting in p-aminonzoie acid in anydesired order for the hydrogen atom of the carboxyl group an alkammeresidue and for a hydrogen atom of the amino group an alkylor analkyloxyalkyl resldue containing more than two carbon atoms and thenconverting the bases so obtained into their water soluble salts.

2. The process for preparing p-N-methoxyethylaminobenzoic acidalkaminester, which consists in substituting in p-aminobenzoic acid, inany desired order, for the hydrogen atom of the carboxyl group analkamme residue and for a hydrogen atom of the amino group themethoxy-ethyl residue, and then converting the bases so obtained intotheir water soluble salts.

3. The process for preparing p-N-alkylaminobenzoic acidpiperidi'no-ethylester, which consists in substituting in p-aminobenzoic acid, in any desired order, for the hydrogen atom of thecarboxyl group the pipe'ridino-ethyl residue and for a hydrogen atom ofthe amino group an alkylor alkyloxyalkyl residue containing more thantwo carbon atoms, and then converting the bases so obtained into theirwater. soluble salts.

4. The process for preparing p-N-methoxyethylaminobenzoic acidiperidino-ethylester, which consists in su stituting in paminobenzoicacid, in any desired order, for the hydrogen atom of the carboxyl groupthe piperidino-ethyl residueand for a h drogen atom of the amino groupthe me oxyethyl residue, and then convertin the base so obtained intoits water solub e salts.

5. The process for preparing p-N-methoxyethylaminobenzoic acidpiperidino-ethylaminobenzoic acid, in any desired order, for

wherein R stands for an alkamine residue, R for an alkylor alkyloxyresidue and X for an acid which renders the bodies water soluble.

7. As new products, the bodies of the formula:

wherein R stands for an alkamine residue and X for an acid which rendersthe bodies water soluble.

ester, which consists in substituting in p- 5 the hydrogen atom of thecarboxyl group' 8; As new products, the bodies of the wherein R standsfor an alkylor alkyloxy residue, X for an acid which renders the bodieswater soluble.

9. As new products, the bodies of the formula:

N-CH -CHgD CHg,

' wherein X stands for an acid which renders the bodies water soluble.

10. As a new product, the body of the formula:

Hg-CH COO .0111 .N CH JICI RFC In testimony whereof, I a my si QTTO E1 70 ature. EB.

